Fluoropicolinoyl fluorides and processes for their preparation

ABSTRACT

Provided herein are fluoropicolinoyl fluorides and processes for their preparation. In some embodiments, provided herein is a process for the preparation of 5-fluoro-6-aryl-picolinoyl fluorides from chloropicolinoyl chlorides.

1. CLAIM OF PRIORITY

Priority is claimed herein to U.S. Provisional Application No.61/675,229 entitled “Fluoropicolinoyl Fluorides and Processes for theirPreparation,” filed Jul. 24, 2012. The above-referenced application isincorporated by reference herein in its entirety.

2. FIELD

Provided herein are fluoropicolinoyl fluorides and processes for theirpreparation. In some embodiments, provided herein is a process for thepreparation of 5-fluoro-6-aryl-picolinoyl fluorides fromchloropicolinoyl chlorides.

3. BACKGROUND

U.S. Pat. No. 6,297,197 B1 describes inter alia certain 6-(alkoxy oraryloxy)-4-amino-3-chloro-5-fluoropicolinate compounds and their use asherbicides. U.S. Pat. Nos. 6,784,137 B2 and 7,314,849 B2 describe interalia certain 6-(aryl)-4-amino-3-chloro-5-fluoropicolinate compounds andtheir use as herbicides. U.S. Pat. No. 7,432,227 B2 describes inter aliacertain 6-(alkyl)-4-amino-3-chloro-5-fluoropicolinate compounds andtheir use as herbicides. Each of these patents describes the manufactureof 4-amino-3-chloro-5-fluoropicolinate starting materials byfluorination of the corresponding 5-unsubstituted pyridines with1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate). It would be advantageous to provide more directand efficient methods for the preparation of4-amino-5-fluoro-3-halo-6-(substituted)picolinates and relatedcompounds, e.g., by the use of reagents and/or chemical intermediateswhich provide improve time and cost efficiency.

4. SUMMARY OF THE DISCLOSURE

Provided herein are fluoropicolinoyl fluorides and processes for theirpreparation. In one embodiment, provided herein is a process for thepreparation of a compound of the Formula I:

-   -   wherein    -   R is selected from the group consisting of halo; alkyl;        cycloalkyl; alkenyl;    -   alkynyl; alkoxy and aryl substituted with from 0 to 5        substituents independently selected from halo, C₁-C₄ alkyl,        C₁-C₄ haloalkyl, C₁-C₄ alkoxy and C₁-C₄ haloalkoxy;    -   m is 0, 1, 2 or 3; and    -   n is 1, 2, 3 or 4;    -   wherein the sum of m and n is less than or equal to 4;        which comprises fluorinating a compound of Formula A:

-   -   wherein R, m and n are as previously defined;        with a source of fluoride ion to produce the compound of the        Formula I.

Fluoropicolinoyl fluorides provided herein may be prepared fromchloropicolinoyl chlorides as shown in Scheme 1 below.

In Scheme 1, “M-F” represents a metal fluoride salt, including but notlimited to, sodium fluoride, potassium fluoride or cesium fluoride. Incertain embodiments, the solvent is sulfolane or acetonitrile.

In other embodiments, provided herein is a process for the preparationof fluoro-6-aryl-picolinoyl fluorides from chloro-6-aryl-picolinoyl acidchlorides as shown in Scheme 2 below.

In Scheme 2, “M-F” represents a metal fluoride salt, including but notlimited to, sodium fluoride, potassium fluoride or cesium fluoride. Incertain embodiments, the solvent is sulfolane or acetonitrile. “Ar”represents an aryl group.

5. DETAILED DESCRIPTION

Provided herein are fluoropicolinoyl fluorides and processes for theirpreparation. In one embodiment, provided herein is a process for thepreparation of a compound of the Formula I:

-   -   wherein    -   R is selected from the group consisting of halo; alkyl;        cycloalkyl; alkenyl; alkynyl; alkoxy and aryl substituted with        from 0 to 5 substituents independently selected from halo, C₁-C₄        alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy and C₁-C₄ haloalkoxy;    -   m is 0, 1, 2 or 3; and    -   n is 1, 2, 3 or 4;    -   wherein the sum of m and n is less than or equal to 4;        which comprises fluorinating a compound of Formula A:

-   -   wherein R, m and n are as previously defined;        with a source of fluoride ion to produce the compound of the        Formula I.

In some embodiments, provided herein is a process for the preparation ofa compound of the Formula I, wherein m is 0. In other embodiments, m is1.

In some embodiments, provided herein is a process for the preparation ofa compound of the Formula I, wherein n is 1, 2 or 3. In someembodiments, n is 2 or 3. In other embodiments, n is 2. In otherembodiments, n is 3.

In some embodiments, the compound of Formula I is:

-   -   wherein R is aryl substituted with from 0 to 5 substituents        independently selected from halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl,        C₁-C₄ alkoxy and C₁-C₄ haloalkoxy; and    -   n is 1, 2 or 3.

In some embodiments, the compound of Formula I is:

-   -   wherein R is phenyl substituted with from 0 to 5 substituents        independently selected from halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl,        C₁-C₄ alkoxy and C₁-C₄ haloalkoxy.

In some embodiments, the process includes a catalyst selected from acrown ether, a phosphonium halide, a polyether, a phosphazenium salt,and a tetra-substituted ammonium halide. In certain embodiments, thecatalyst is a crown ether. In one embodiment, the crown ether is18-crown-6.

In some embodiments, the source of fluoride ion is a metal fluoride. Insome embodiments, the metal fluoride is selected from sodium fluoride,potassium fluoride and cesium fluoride. In one embodiment, the metalfluoride is potassium fluoride.

In some embodiments, the process includes a solvent. In someembodiments, the solvent is selected from an alkyl nitrile or an alkylsulfone. In certain embodiments, the solvent is acetonitrile orsulfolane.

In one embodiment, provided herein is a process for the preparation of acompound of the formula:

-   -   wherein    -   R is phenyl substituted with from 0 to 5 substituents        independently selected from halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl,        C₁-C₄ alkoxy and C₁-C₄ haloalkoxy; and    -   n is 1 or 2;        which comprises reacting a compound of Formula A:

-   -   wherein R is phenyl substituted with from 0 to 5 substituents        independently selected from halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl,        C₁-C₄ alkoxy and C₁-C₄ haloalkoxy; and    -   n is 1 or 2;        with potassium fluoride in the presence of a crown ether and a        solvent.

In one embodiment, the solvent is acetonitrile or sulfolane.

Also provided herein is a compound of the Formula I:

-   -   wherein    -   R is selected from the group consisting of halo; alkyl;        cycloalkyl; alkenyl; alkynyl; alkoxy and aryl substituted with        from 0 to 5 substituents independently selected from halo, C₁-C₄        alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy and C₁-C₄ haloalkoxy;    -   m is 0, 1, 2 or 3; and    -   n is 0, 1, 2, 3 or 4;        wherein the sum of m and n is between 1 and 4.

In one embodiment, m is 0 and n is 1, 2, 3 or 4.

In another embodiment, the compound is of the formula:

In another embodiment, the compound is of the formula:

-   -   wherein R is aryl substituted with from 0 to 5 substituents        independently selected from halogen, C₁-C₄ alkyl, C₁-C₄        haloalkyl, C₁-C₄ alkoxy and C₁-C₄ haloalkoxy; and    -   n is 1, 2 or 3. In one embodiment, n is 1 or 2.

In another embodiment, the compound is of the formula:

In another embodiment, provided herein is a process for the preparationof a compound of the Formula II:

-   -   wherein    -   R is selected from the group consisting of halo; alkyl;        cycloalkyl; alkenyl; alkynyl; alkoxy and aryl substituted with        from 0 to 5 substituents independently selected from halo, C₁-C₄        alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy and C₁-C₄ haloalkoxy;    -   R¹ is selected from the group consisting of H; alkyl;        cycloalkyl; alkenyl; alkynyl; and aryl substituted with from 0        to 5 substituents independently selected from halo, C₁-C₄ alkyl,        C₁-C₄ haloalkyl, C₁-C₄ alkoxy and C₁-C₄ haloalkoxy;    -   m is 0, 1, 2 or 3; and    -   n is 0, 1, 2, 3 or 4;        wherein the sum of m and n is between 1 and 4;        which comprises (a) fluorinating a compound of Formula A:

with a source of fluoride ion to produce a compound of the Formula I:

-   -   wherein R is selected from the group consisting of halo; alkyl;        cycloalkyl; alkenyl; alkynyl; alkoxy and aryl substituted with        from 0 to 5 substituents independently selected from halo, C₁-C₄        alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy and C₁-C₄ haloalkoxy;    -   m is 0, 1, 2 or 3; and    -   n is 0, 1, 2, 3 or 4;        which further comprises (b) reacting a compound for Formula I        with a source of R¹OH to produce a compound of Formula II.

In another embodiment, provided herein is a process for the preparationof a compound of the Formula II:

-   -   wherein    -   R is selected from the group consisting of halo; alkyl;        cycloalkyl; alkenyl; alkynyl; alkoxy and aryl substituted with        from 0 to 5 substituents independently selected from halo, C₁-C₄        alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy and C₁-C₄ haloalkoxy;    -   R¹ is selected from the group consisting of H; alkyl;        cycloalkyl; alkenyl; alkynyl; unsubstituted or substituted        C₇-C₁₁ arylalkyl; and aryl substituted with from 0 to 5        substituents independently selected from halo, C₁-C₄ alkyl,        C₁-C₄ haloalkyl, C₁-C₄ alkoxy and C₁-C₄ haloalkoxy;    -   m is 0, 1, 2 or 3; and    -   n is 0, 1, 2, 3 or 4;        wherein the sum of m and n is between 1 and 4;        which comprises (a) fluorinating a compound of Formula A:

with a source of fluoride ion to produce a compound of the Formula I:

-   -   wherein R is selected from the group consisting of halo; alkyl;        cycloalkyl; alkenyl; alkynyl; alkoxy and aryl substituted with        from 0 to 5 substituents independently selected from halo, C₁-C₄        alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy and C₁-C₄ haloalkoxy;    -   m is 0, 1, 2 or 3; and    -   n is 0, 1, 2, 3 or 4;        which further comprises (b) reacting a compound for Formula I        with a source of R¹OH to produce a compound of Formula II.

In some embodiments, the reaction of step (b) further comprises a base.In some embodiments, the base is a trialkyl amine base, e.g.,triethylamine.

Fluoropicolinoyl fluorides provided herein may be prepared fromchloropicolinoyl chlorides as shown in Scheme 1 below.

In Scheme 1, “M-F” represents a metal fluoride salt, including but notlimited to, sodium fluoride, potassium fluoride or cesium fluoride. Incertain embodiments, the solvent is sulfolane or acetonitrile.

In other embodiments, provided herein is a process for the preparationof fluoro-6-aryl-picolinoyl fluorides from chloro-6-aryl-picolinoyl acidchlorides as shown in Scheme 2 below. “Ar” represents an aryl group.

In Scheme 2, “M-F” represents a metal fluoride salt, including but notlimited to, sodium fluoride, potassium fluoride or cesium fluoride. Incertain embodiments, the solvent is sulfolane or acetonitrile. “Ar”represents an aryl group.

The fluoropicolinoyl fluorides provided herein may be used asintermediates in the preparation of picolinate acids and esters, whichin turn may be used as intermediates in the preparation of4-amino-5-fluoro-3-halo-6-aryl-picolinates such as4-amino-3-chloro-5-fluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylicacid.

Schemes 3 and 4 are non-limiting examples of the processes providedherein. Carboxylic acid or ester derivatives of the picolinoyl fluoridesprovided herein may be prepared according to Schemes 3 and 4 as desiredproducts, or to further characterize the picolinoyl fluorides, as insome instances, the picolinoyl fluorides are not stable to certainconventional purification methods. In most cases, the picolinoylfluorides were characterized by GC/MS and ¹⁹F NMR analysis withoutpurification. 4,5,6-trifluoropicolinoyl fluoride was isolated bydistillation and characterized by GC/MS and NMR techniques. The estersand carboxylic acids provided below were purified and characterized byGC/MS and NMR techniques.

Schemes 3 and 4 provide direct access to di-, tri- andtetra-fluoropicolinoyl fluorides in good yields. Previous methods, asillustrated in Scheme 5, resulted in complex mixtures of undesiredproducts. Thus, the processes provided herein represent and improvedprocess for access to di-, tri- and tetra-fluoropicolinates.

The mono-, di-, tri, and tetra-chloropicolinoyl chloride and/or6-aryl-picolinoyl chloride starting materials provided herein are knowncompounds, and/or may be prepared from known chloropicolinates usingroutine techniques known in the art. See, e.g., U.S. Pat. No. 6,784,137B2. Higher esters, including unsubstituted or substituted C₇-C₁₁arylalkyl esters, can be prepared by direct esterification ortransesterification reactions using techniques which are well known inthe art. An exemplary scheme for the preparation of a 6-aryl-picolinoylchloride is shown below:

Fluoride ion sources which may be used in processes provided hereininclude alkali metal fluorides (“M-F”), which include sodium fluoride(NaF), potassium fluoride (KF) and cesium fluoride (CsF). Fluoride saltssuch as tetrabutylammonium fluoride (n-Bu₄NF) may also be used.

In some embodiments, the reactions are carried out in a solvent orreaction medium such as, acetonitrile, sulfolane, alkyl nitriles,polyethers, or alkyl sulfones, including mixtures thereof. In certainembodiments, the solvent used is an alkyl nitrile or an alkyl sulfone.In certain embodiments, the solvent used is acetonitrile or sulfolane.

Catalysts such as crown ethers or phase transfer agents which are knownto increase the rate of fluoride exchange may also be used. In someembodiments, the catalyst is a crown ether, a phosphonium halide, apolyether, a phosphazenium salt, or a tetra-substituted ammonium halide.In certain embodiments, the catalyst is a crown ether, e.g., 18-crown-6.

The temperature at which the reaction is conducted is not critical. Incertain embodiments, the temperature is from about 50° C. to about 200°C., and in some embodiments, from about 80° C. to about 140° C.Depending upon which solvent is employed in a particular reaction, theoptimum temperature will vary. Generally speaking the lower thetemperature the slower the reaction will proceed. Exemplary reactionsare conducted in the presence of vigorous agitation sufficient tomaintain an essentially uniformly dispersed mixture of the reactants.

In conducting the reaction, neither the rate, nor the order, of additionof the reactants is critical. In some embodiments, the solvent andalkali metal fluoride, and optionally, the catalyst, are mixed beforethe picolinoyl chloride is added to the reaction mixture. In certainembodiments, the reaction requires from about 2 to about 100 hours andis conducted at ambient atmospheric pressure. In some embodiments, thereaction is conducted at a pressure up to and including 500 psi.

While the exact amount of reactants is not critical, in some embodimentsan amount of alkali metal fluoride is provided which will supply atleast about an equimolar amount of fluorine atoms based on the number ofchlorine atoms to be exchanged in the starting material, i.e., at leastan equimolar amount of alkali metal fluoride.

The products obtained by any of the processes provided herein may berecovered by conventional means, such as evaporation or extraction, andmay be purified by standard procedures, such as distillation,recrystallization or chromatography.

DEFINITIONS

The terms “alkyl,” “alkenyl” and “alkynyl,” as well as derivative termssuch as “alkoxy,” “acyl,” “alkylthio” and “alkylsulfonyl” as usedherein, include within their scope straight chain, branched chain andcyclic moieties, and include moieties having one to twelve carbon atoms.In certain embodiments, “alkyl,” “alkoxy,” “acyl,” “alkylthio” and“alkylsulfonyl” each contain one to six carbon atoms or alternatively,one to four carbon atoms. In certain embodiments, “alkenyl” and“alkynyl” each contain two to six carbon atoms or alternatively, two tofour carbon atoms.

Unless specifically stated otherwise, each of alkyl,” “alkenyl” and“alkynyl,” as well as derivative terms such as “alkoxy,” “acyl,”“alkylthio” and “alkylsulfonyl” may be unsubstituted or substituted withone or more substituents selected from but not limited to halogen,hydroxy, C₁-C₆ alkoxy, C₁-C₆ alkylthio, C₁-C₆ acyl, formyl, cyano,aryloxy or aryl, provided that the substituents are stericallycompatible and the rules of chemical bonding and strain energy aresatisfied. The terms “alkenyl” and “alkynyl” are intended to include oneor more unsaturated bonds.

The term “aryl,” as used herein, refers to a 6-14 membered aromaticcarbocylic group, e.g., phenyl or naphthyl. The aryl group may beunsubstituted or substituted with one or more substituents independentlyselected from halogen, nitro, cyano, C₁-C₆ alkyl, C₁-C₆ alkoxy,halogenated C₁-C₆ alkyl, halogenated C₁-C₆ alkoxy, C₁-C₆ alkylthio,C(O)OC₁-C₆ alkyl, or where two adjacent substituents are taken togetheras —O(CH₂)_(n)O— wherein n=1 or 2.

The term “arylalkyl,” as used herein, refers to a phenyl substitutedalkyl group having a total of 7 to 11 carbon atoms, such as benzyl(—CH₂C₆H₅), 2-methylnaphthyl (—CH₂C₁₀H₇) and 1- or 2-phenethyl(—CH₂CH₂C₆H₅ or —CH(CH₃)C₆H₅). The phenyl group may itself beunsubstituted or substituted with one or more substituents independentlyselected from halogen, nitro, cyano, C₁-C₆ alkyl, C₁-C₆ alkoxy,halogenated C₁-C₆ alkyl, halogenated C₁-C₆ alkoxy, C₁-C₆ alkylthio,C(O)OC₁-C₆alkyl, or where two adjacent substituents are taken togetheras —O(CH₂)_(n)O— wherein n=1 or 2, provided that the substituents aresterically compatible and the rules of chemical bonding and strainenergy are satisfied.

6-Aryl groups provided herein may be substituted with from 1 to 4substituents independently selected from halogen, C₁-C₄ alkyl, C₁-C₄haloalkyl, C₁-C₄ alkoxy or C₁-C₄ haloalkoxy. In certain embodiments, thesubstitution pattern is selected from 4-substituted phenyl,2,4-disubstituted phenyl, 2,3,4-trisubstituted phenyl,2,4,5-trisubstituted phenyl, and 2,3,4,6-tetrasubstituted phenyl.

Unless specified otherwise, the term “halogen,” as well as derivativeterms such as “halo,” refers to fluorine, chlorine, bromine and iodine.

6. EXAMPLES Example 1 4,5,6-trifluoropicolinoyl fluoride

A 1-liter three neck round bottom flask was purged with N₂ and fittedwith a condenser/N₂ bubbler, mechanical stirrer and a stopper. To thereactor was add anhydrous CsF (172 g, 1.13 mol), dry acetonitrile (400mL), 18-crown-6 (6.0 g, 0.023 mol) and the 4,5,6-trichloropicolinoylchloride (55 g, 0.23 mol). The mixture was heated to reflux and heldthere for 20 h. The slurry was cooled to room temperature and the saltsfiltered under N₂ pressure. The salt cake was rinsed with dryacetonitrile (100 mL) to give an amber liquid (372 g). A three neck N₂purged 250 mL round bottom flask with thermowell was fitted with twostoppers, a magnetic stir bar and a vacuum jacketed Vigruex distillationcolumn (15 cm×1 cm) with fraction collector connected to a N₂ bubbler.To the vessel was added 140 g of the acetonitrile solution from above.The distillation vessel was heated to 82-85° C. while a clear colorlessdistillate (acetonitrile) was collected overhead at 80-83° C. When thedistillation pot temperature began to rise and the head temperaturebegan to fall the distillation was terminated and allowed to cool toroom temperature under N₂. The distillation pot residue was quicklytransferred to a N₂ purged two neck 25 mL round bottom flask. The flaskwas fitted with a thermometer, magnetic stir bar and the samedistillation set up described above. This distillation system could ventto vacuum or N₂. Vacuum (ca. 70 mmHg) was established and then heatingof the distillation vessel commenced. The product was collected as aclear colorless liquid (6.7 g, bp 55-60° C. @ 55-60 mmHg). GC areapercent analysis showed the material to be 99.1% pure: ¹H NMR (CDCl₃,400 MHz, ppm) δ 8.08 (ddd, J=8.4, 4.4, 0.4 Hz); ¹³C NMR (101 MHz, CDCl₃,ppm) δ 157.71 (dt, J=269.0, 6.5 Hz), 152.96 (dd, J=246.1, 13.4 Hz),152.49 (d, J=348.6 Hz), 138.69 (ddd, J=275.3, 30.2, 12.9 Hz), 135.44(dddd, J=74.6, 15.1, 7.8 Hz), 117.00 (dt, J=18.2, 4.2 Hz); MS (GC, 70 eVelectron impact) 179 (M⁺, 100%), 160 (8%), 151 (100%), 132 (80%), 82(63%).

In another experiment as described above, after the filtration and saltcake wash, 366 g of amber solution was obtained. Area percent GCanalysis indicated the mixture was 86.4% 4,5,6-trifluoropicolinoylfluoride and 13.6% 18-crown-6. An internal standard GC analysis methodwas developed using dimethyl phthalate as the internal standard and thematerial prepared above as the pure component. GC assay of the ambersolution indicated it was 9.8 wt. % product which correlated to a yieldof 89%.

Example 2 4,5,6-trifluoropicolinic acid

4,5,6-Trifluoropicolinoyl fluoride (300 mg) was allowed to stand in airfor six days providing the carboxylic acid (250 mg) as a white solid: mp81-82° C.; ¹H NMR (400 MHz, acetone-d₆) δ 8.07 (dd, J=9.2, 4.8 Hz); ¹³CNMR (101 MHz, acetone-d₆) δ 163.4 (d, J=3.2 Hz), 158.6 (ddd, J=263.8,9.0, 5.8 Hz), 152.9 (ddd, J=237.2, 12.1, 4.7 Hz), 142.2 (m), 138.2 (ddd,J=267.2, 31.4, 13.5 Hz), 115.2 (dd, J=17.6, 5.2 Hz); MS (GC, 70 eV EI)177 (M+, 1%), 160 (5%), 133 (100%), 132 (40%), 106 (40%), 82 (30%).

Example 3 Isopropyl 3,4,5,6-tetrafluoropicolinate

The reaction was carried out in a nitrogen atmosphere glove box. To aglass jar equipped with a stir bar was added3,4,5,6-tetrachloropicolinoyl chloride (1.117 g, 4 mmol), 18-crown-6(0.106 g, 0.4 mmol), KF (1.859 g, 32 mmol) and sulfolane (pre-dried, 15g). The mixture was heated to 130° C. on a heating block for 21 hours. Asample was taken and analyzed by GC, GC/MS and ¹⁹F NMR. GC showed thisreaction was complete. GC/MS results were consistent with the chemicalformula of 3,4,5,6-tetrafluoropicolinoyl fluoride: 70 eV EIMS (GC)m/z=197 (M⁺, 91%), 169 (100%), 150 (51%), 100 (100%). ¹⁹F NMR (376 MHz,CD₃CN) δ 26.57 (d, J=38.1 Hz), −81.71 (dd, J=44.1, 24.4 Hz), −133.00 to−134.26 (m), −136.54 to −136.69 (m), −145.62 to −145.77 (m).

Anhydrous 2-propanol (0.361 g, 6 mmol) and anhydrous tri-ethylamine(0.405 g, 4 mmol) were added drop-wise at room temperature to the3,4,5,6-tetrafluoropicolinoyl fluoride provided above. The mixture wasstirred at room temperature overnight, poured into a reparatory funnelwith water and extracted with ethyl ether. The organic phase was thenwashed with water and dried over MgSO₄. The solvent was removed with arotary evaporator. The concentrated crude product was purified usingcolumn chromatography (silica gel) with ethyl acetate/hexanes mixture(1/10) as eluent to give 0.454 g (48% yield, 96% GC purity, 93% LCpurity) of desired product as a pale yellow liquid. GC/MS results wereconsistent with the chemical formula of isopropyl3,4,5,6-tetrafluoropicolinate: 70 eV EIMS (GC) m/z=196 (31%), 178(100%), 150 (45%), 100 (26%), 43 (34%). ¹H NMR (400 MHz, CDCl₃) δ 5.32(hept, J=6.3 Hz, 1H), 1.42 (d, J=6.3 Hz, 6H). ¹³C NMR (101 MHz, CDCl₃) δ159.81 to 159.74 (m), 149.22 to 148.78 (m), 148.04 to 147.86 (m), 146.49to 146.10 (m), 145.65 to 145.47 (m), 138.53 (dd, J=34.3, 11.2 Hz),135.79 (dd, J=34.4, 11.2 Hz), 129.02 to 128.74 (m), 70.97 (s), 21.60(s). ¹⁹F NMR (376 MHz, CDCl₃) δ −80.31 to −80.49 (m), −136.04 to −136.18(m), −137.10 to −137.25 (m), −149.81 to −149.95 (m).

Alternatively, the above reaction was performed in acetonitrile ratherthan sulfolane. A 100 mL Parr reactor (Hastelloy C construction) wascleaned, dried and leak tested under nitrogen. To the vessel was added3,4,5,6-tetrachloropicolinoyl chloride (5.587 g, 20 mmol), 18-crown-6(0.529 g, 2 mmol), KF (10.458 g, 180 mmol) and anhydrous acetonitrile(45 g). The entire system was purged with nitrogen. The reaction mixturewas stirred at 135° C. for 20 hours, and then was allowed to cool tobelow 45° C. The system was slowly vented. A sample was taken andanalyzed by GC, GC/MS and 19F NMR. GC showed this reaction was complete.GC/MS results were consistent with the chemical formula of3,4,5,6-tetrafluoropicolinoyl fluoride: 70 eV EIMS (GC) m/z=197 (M+,86%), 169 (98%), 150 (51%), 100 (100%). ¹⁹F NMR (376 MHz, CD3CN) δ 26.34(d, J=38.3 Hz), −81.98 (dd, J=44.2, 23.6 Hz), −134.35 to −134.57 (m),−136.94 to −137.09 (m), −146.02 to −146.17 (m).

Anhydrous 2-propanol (1.803 g, 30 mmol) and anhydrous tri-ethylamine(2.024 g, 20 mmol) were added drop-wise at 5-10° C. to the solution of3,4,5,6-tetrafluoropicolinoyl fluoride provided above. The mixture wasstirred at room temperature overnight. The mixture was discharged fromthe vessel and the salts were removed by filtration and washed with alittle acetonitrile. The solvent was removed with a rotary evaporator.The crude mixture was re-dissolved in ethyl ether. The organic phase wasthen washed with water and dried over MgSO₄. The solvent was removedwith a rotary evaporator. The concentrated crude product was purifiedusing column chromatography (silica gel) with ethyl acetate/hexanesmixture (4/50) as eluent to give 3.77 g (79% yield, 99% GC purity, 97%LC purity) of desired product as a pale yellow liquid. GC/MS resultswere consistent with the chemical formula of isopropyl3,4,5,6-tetrafluoropicolinate: 70 eV EIMS (GC) m/z=196 (32%), 178(100%), 150 (49%), 100 (33%), 43 (75%). ¹H NMR (400 MHz, CDCl₃) δ 5.32(hept, J=6.3 Hz, 1H), 1.42 (d, J=6.3 Hz, 6H). ¹³C NMR (101 MHz, CDCl₃) δ159.82 to 159.74 (m), 149.22 to 148.85 (m), 148.02 to 147.89 (m), 146.47to 146.17 (m), 145.63 to 145.47 (m), 138.54 (dd, J=34.3, 11.2 Hz),135.79 (dd, J=34.3, 11.4 Hz), 129.03 to 128.74 (m), 70.98 (s), 21.61(s). ¹⁹F NMR (376 MHz, CDCl₃) δ −80.26 to −80.44 (m), −135.99 to −136.13(m), −137.07 to −137.22 (m), −149.77 to −149.91 (m).

Example 4 Isopropyl 5-fluoropicolinate

The reaction was carried out in a nitrogen atmosphere glove box. To aglass jar equipped with a stir bar was added 5-chloropicolinoyl chloride(0.704 g, 4 mmol), 18-crown-6 (0.106 g, 0.4 mmol), KF (0.744 g, 12.8mmol) and sulfolane (pre-dried, 8 g). The mixture was heated to 130° C.on a heating block for 19 hours. A sample was taken and analyzed by GC.The results showed that the reaction was not complete, thereforeadditional KF (0.232 g, 4 mmol) was added and the mixture was heated to130° C. for additional 22 hours. A sample was analyzed by GC, GC/MS and¹⁹F NMR. GC showed this reaction was complete. GC/MS results wereconsistent with the chemical formula of 5-fluoropicolinoyl fluoride: 70eV EIMS (GC) m/z=143 (M⁺, 100%), 115 (55%), 96 (90%), 76 (46%). ¹⁹F NMR(376 MHz, CD₃CN) δ 16.01 (s), −117.57 (s).

Anhydrous 2-propanol (0.361 g, 6 mmol) and anhydrous tri-ethylamine(0.405 g, 4 mmol) were added drop-wise at room temperature to the5-fluoropicolinoyl fluoride provided above. The mixture was stirred atroom temperature overnight, poured into a reparatory funnel with waterand extracted with ethyl ether. The organic phase was then washed withwater and dried over MgSO₄. The solvent was removed with a rotaryevaporator. The concentrated crude product was purified using columnchromatography (silica gel) with ethyl acetate/hexanes mixture (1/10) aseluent to give 0.17 g (23% yield, 96% LC purity) of desired product asan off-white solid. GC/MS results were consistent with the chemicalformula of isopropyl 5-fluoropicolinate: 70 eV EIMS (GC) m/z=142 (43%),124 (100%), 97 (97%), 96 (93%), 43 (59%). ¹H NMR (400 MHz, CDCl₃) δ 8.60(d, J=2.8 Hz, 1H), 8.18 (dd, J=8.8, 4.4 Hz, 1H), 7.52 (ddd, J=8.7, 7.9,2.9 Hz, 1H), 5.34 (hept, J=6.3 Hz, 1H), 1.43 (d, J=6.3 Hz, 6H). ¹³C NMR(101 MHz, CDCl₃) δ 163.63 (s), 162.32 (s), 159.71 (s), 144.84 (d, J=3.8Hz), 138.46 (d, J=24.8 Hz), 126.78 (d, J=5.4 Hz), 123.31 (d, J=18.5 Hz),69.71 (s), 21.81 (s). ¹⁹F NMR (376 MHz, CDCl₃) δ −120.51.

Example 5 Isopropyl 3,6-difluoropicolinate

The reaction was carried out in a nitrogen atmosphere glove box. To aglass jar equipped with a stir bar was added 3,6-dichloropicolinoylchloride (0.842 g, 4 mmol), 18-crown-6 (0.106 g, 0.4 mmol), KF (1.394 g,24 mmol) and sulfolane (pre-dried, 9 g). The mixture was heated to 130°C. on a heating block for 22 hours. A sample was taken and analyzed byGC. The results showed that the reaction was not complete, thereforeadditional KF (0.348 g, 6 mmol) was added and mixture was heated to 130°C. for additional 22 hours. A sample was analyzed by GC, GC/MS and ¹⁹FNMR. GC showed this reaction was complete. GC/MS results were consistentwith the chemical formula of 3,6-difluoropicolinoyl fluoride: 70 eV EIMS(GC) m/z=161 (M⁺, 73%), 133 (100%), 114 (44%), 64 (60%). ¹⁹F NMR (376MHz, CD₃CN) δ 26.30 (d, J=36.4 Hz), −70.56 (d, J=25.9 Hz), −119.36 (dd,J=36.4, 26.0 Hz).

Anhydrous 2-propanol (0.361 g, 6 mmol) and anhydrous tri-ethylamine(0.405 g, 4 mmol) were added dropwise at room temperature to the3,6-difluoropicolinoyl fluoride provided above. The mixture was stirredat room temperature for 6 hours, poured into a reparatory funnel withwater and extracted with ethyl ether. The organic phase was then washedwith water and dried over MgSO₄. The solvent was removed with a rotaryevaporator. The concentrated crude product was purified using columnchromatography (silica gel) with ethyl acetate/hexanes mixture (1/10) aseluent to give 0.39 g (48% yield, 99% GC purity, 98% LC purity) ofdesired product as a pale yellow liquid. GC/MS results were consistentwith the chemical formula of isopropyl 3,6-difluoropicolinate: 70 eVEIMS (GC) m/z=160 (41%), 142 (100%), 115 (43%), 114 (66%), 64 (31%), 43(51%). ¹H NMR (400 MHz, CDCl₃) δ 7.69 to 7.63 (m, 1H), 7.16 to 7.12 (m),5.33 (hept, J=6.3 Hz, 1H), 1.41 (d, J=6.3 Hz, 6H). ¹³C NMR (101 MHz,CDCl₃) δ 161.41 (d, J=6.3 Hz), 158.80 (d, J=1.2 Hz), 158.26 (d, J=4.3Hz), 156.41 (d, J=1.2 Hz), 155.62 (d, J=4.4 Hz), 134.05 (t, J=13.5 Hz),131.06 (dd, J=23.9, 8.3 Hz), 114.86 (dd, J=41.7, 5.9 Hz), 70.34 (s),21.71 (s). ¹⁹F NMR (376 MHz, CDCl₃) δ −69.40 (d, J=26.9 Hz), −122.76 (d,J=27.4 Hz).

Example 6 Isopropyl 4,5-difluoro-6-(4-chlorophenyl)picolinate

To a solution of 4,5-dichloro-6-(4-chlorophenyl)picolinoyl chloride (2.0g, 6.23 mmol) in sulfolane (40 mL, dried over 4 Å molecular sieves, 100ppm H₂O) was added potassium fluoride (2.2 g, 37.4 mmol). The reactionmixture was heated at 130° C. for 24 h. Reaction mixture was analyzed byGC-MS and ¹⁹F NMR. (Data for 6-(4-chlorophenyl)-4,5-difluoropicolinoylfluoride, GC-MS: m/z=271, 223; ¹⁹F NMR (376 MHz, Toluene-d8) δ 17.05(s), −123.81 (d, J=19.1 Hz), −140.17 (d, J=19.1 Hz). Reaction wasallowed to cool to room temperature and triethylamine (1.1 mL, 7.8 mmol)and isopropanol (0.7 mL, 9.4 mmol) were added. After stirring for 1.5 h,the reaction mixture was diluted with water (100 mL) and transferred toa separatory funnel. The reaction mixture was extracted with methyltert-butyl ether (MTBE, 2×50 mL). The combined organic extracts werewashed with water (3×50 mL) and saturated aqueous NaCl solution (50 mL)and concentrated under reduced pressure to provide a brown oil. Thecrude product oil was purified by silica gel flash chromatography(hexane/ethyl acetate gradient, 100% hexane→20% hexane/ethyl acetate) toprovide 0.93 g (48% yield) of isopropyl6-(4-chlorophenyl)-4,5-difluoropicolinate as a white solid. ¹H NMR (400MHz, CDCl₃) δ 8.04-7.98 (m, 2H), 7.90 (dd, J=9.4, 5.3 Hz, 1H), 7.51-7.45(m, 2H), 5.31 (hept, J=6.3 Hz, 1H), 1.43 (d, J=6.3 Hz, 6H). 13C NMR (101MHz, CDCl3) δ 162.72 (d, J=3.5 Hz), 158.12 (d, J=12.6 Hz), 155.49 (d,J=12.4 Hz), 149.41 (d, J=11.0 Hz), 147.16 (dd, J=7.9, 1.0 Hz), 146.73(d, J=10.9 Hz), 136.51 (d, J=0.9 Hz), 130.34 (d, J=6.6 Hz) 128.93 (s),113.80 (d, J=16.1 Hz), 70.25 (s), 21.85 (s). 19F NMR (376 MHz, CDCl3) δ−124.73 (dd, J=17.7, 9.5 Hz), −144.38 (dd, J=17.7, 5.4 Hz). LRMS. Calcd.C₁₆H₁₅F₂NO₃: 307.10. Found: m/z=307 (M+), 221, 206. MP. 73-74° C.

Example 7 Isopropyl 4,5-difluoro-6-phenylpicolinate

To a solution of 4,5-dichloro-6-phenylpicolinoyl chloride (1.76 g, 6.14mmol) in sulfolane (40 mL, dried over 4 Å molecular sieves, ˜100 ppmH₂O) was added potassium fluoride (2.14 g, 36.9 mmol). The reactionmixture was heated at 130° C. for 24 h. Reaction mixture was analyzed byGC-MS and ¹⁹F NMR. (Data for 4,5-difluoro-6-phenylpicolinoyl fluoride,GC-MS: m/z=237, 189; ¹⁹F NMR (376 MHz, Toluene-d8) δ 17.03 (s), −124.14(d, J=19.1 Hz), −140.76 (d, J=19.1 Hz). Reaction was allowed to cool toroom temperature and triethylamine (1.1 mL, 7.7 mmol) and isopropanol(0.7 mL, 9.2 mmol) were added. After stirring for 1.5 h, the reactionmixture was diluted with water (100 mL) and transferred to a separatoryfunnel. The reaction mixture was extracted with methyl tert-butyl ether(MTBE, 2×50 mL). The combined organic extracts were washed with water(3×50 mL) and saturated NaCl (50 mL) and concentrated under reducedpressure to provide a brown oil. The crude product oil was purified bysilica gel flash chromatography (hexane/ethyl acetate gradient, 100%hexane→20% hexane/ethyl acetate) to provide 1.2 g (70% yield) ofisopropyl 4,5-difluoro-6-phenyl-picolinate as a yellow oil. ¹H NMR (400MHz, CDCl₃) δ 8.07-7.99 (m, 2H), 7.89 (dd, J=9.4, 5.3 Hz, 1H), 7.56-7.42(m, 3H), 5.31 (hept, J=6.3 Hz, 1H), 1.43 (d, J=6.3 Hz, 6H). ¹³C NMR (101MHz, CDCl₃) δ 162.89 (d, J=3.4 Hz), 156.74 (dd, J=264.2, 12.5 Hz),148.07 (dd, J=268.9, 10.8 Hz), 146.99 (dd, J=309.2, 10.8 Hz), 145.45(s), 134.12-133.60 (m), 130.20 (s), 129.05 (d, J=5.9 Hz), 128.64 (s),113.56 (d, J=16.0 Hz), 70.14 (s), 21.86 (s). ¹⁹F NMR (376 MHz, CDCl₃) δ−125.22 (dd, J=17.7, 9.5 Hz), −144.74 (dd, J=17.7, 5.4 Hz). LRMS. Calcd.C₁₅H₁₃F₂—NO₂: 277.09. Found: m/z=277 (M⁺), 218, 191.

Example 8 Isopropyl 4,5-difluoro-6-(4-methoxyphenyl)picolinate

To a solution of 4,5-dichloro-6-(4-methoxyphenyl)-picolinoyl chloride(2.5 g, 7.9 mmol) in sulfolane (40 mL, dried over 4 Å molecular sieves,100 ppm of water) was added potassium fluoride (2.75 g, 47.4 mmol). Thereaction mixture was heated at 150° C. for 24 h. Additional potassiumfluoride (1.4 g, 24 mmol) was added and reaction mixture was heated at150° C. for an additional 24 h. Reaction mixture was analyzed by GC-MSand ¹⁹F NMR. (Data for 4,5-difluoro-6-(4-methoxyphenyl)-picolinoylfluoride, GC-MS: m/z=267, 224, 176; ¹⁹F NMR (376 MHz, toluene) δ 16.94(s), −124.65 (d, J=19.1 Hz), −141.23 (d, J=19.1 Hz). Reaction wasallowed to cool to room temperature and triethylamine (1.4 mL, 9.9 mmol)and isopropanol (0.9 mL, 11.9 mmol) were added. After stirring for 1.5h, the reaction mixture was diluted with water (125 mL) and transferredto a reparatory funnel. The reaction mixture was extracted with methyltert-butyl ether (MTBE, 2×75 mL). The combined organic extracts werewashed with water (3×75 mL) and saturated NaCl (75 mL) and concentratedunder reduced pressure to provide a brown oil. The crude product oil waspurified by silica gel flash chromatography (hexane/ethyl acetategradient, 100% hexane→20% hexane/ethyl acetate) to provide 0.60 g (25%yield) of isopropyl 4,5-difluoro-6-(4-methoxyphenyl)-picolinate as apale yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.08-8.01 (m, 2H), 7.82(dd, J=9.5, 5.2 Hz, 1H), 7.04-6.97 (m, 2H), 5.30 (hept, J=6.3 Hz, 1H),3.86 (s, 3H), 1.42 (d, J=6.3 Hz, 6H), ¹³C NMR (101 MHz, CDCl₃) δ 162.93(s), 161.22 (s), 156.68 (dd, J=263.5, 12.7 Hz), 147.70 (dd, J=267.9,10.9 Hz), 146.61 (dd, J=286.4, 10.5 Hz), 145.18 (s), 130.53 (d, J=6.6Hz), 126.43, 114.02 (s), 112.77 (d, J=16.1 Hz), 69.99 (s), 55.32 (s),21.82 (s), ¹⁹F NMR (376 MHz, CDCl₃) δ −125.81 (d, J=17.7 Hz), −145.30(d, J=19.1 Hz), LRMS. Calcd. for C₁₆H₁₅F₂NO₃: 307.10. Found: m/z=307(M⁺), 221, 206.

Example 9 Methyl6-(4-chloro-2-fluoro-3-methoxyphenyl)-4,5-difluoro-2-pyridinecarboxylate

A mixture of 1.74 g (30 mmol, 6 eq) of KF (dried 115° C. with N₂ purgeovernight), 1.85 g (5 mmol) of6-(4-chloro-2-fluoro-3-methoxyphenyl)-4,5-dichloro-2-pyridinecarbonylchloride and 10 mL of sulfolane (dried using 4 Å molecular sieves) washeated at 130° C. for 10 h and then at room temperature overnight. LCarea analysis indicated incomplete reaction (63% product, 15%mono-fluoro intermediates). The mixture was heated at 130° C. foranother 7 h, when LC area analysis indicated 74% product and 4%mono-fluoro intermediates. After cooling to 50° C., 0.24 mL (6 mmol) ofMeOH was added, and the mixture stirred at room temperature overnight.To the amber mixture was added 10 mL of H₂O dropwise over 20 min.Initially, gummy solids formed which eventually dissipated to leave athick, brownish gray mixture. After stirring at room temperature for 15min, the mud-like mixture was filtered (slow), rinsed with 4 mL of 1:1sulfolane/H₂O and 2× with 4 mL of H₂O to give 5.44 g of a brown solid.The solid was dried to give 1.54 g of a tan powder. LC internal standardanalysis indicated a purity of 78.4 wt %, for a yield of 73.0%.

Purification of Methyl6-(4-chloro-2-fluoro-3-methoxyphenyl)-4,5-difluoro-2-pyridinecarboxylate

Material from a previous experiment (1.8 g, 67 area % LC) was heated anddissolved in 15 ml, of toluene. This solution was flash chromatographedon silica (500 g, 70-230 mesh) eluting with toluene. After 10 L oftoluene has passed through the column, product was seen and collectedover the next 2 L of eluent. The toluene fractions containing theproduct were concentrated in vacuo to give 647 mg of a white solid, 94area % purity by LC analysis. This solid was dissolved in 3 mL ofacetonitrile, cooled in a refrigerator, filtered and rinsed with 0.5 mLof cold acetonitrile to give 529 mg of a white solid, mp 134-134° C., 97area % purity by LC analysis. EIMS m/e (relative intensity) 331 (1Cl,50), 273 (1Cl, 100), 238 (46), 237 (28), 222 (14), 194 (48); ¹H NMR (400MHz, CDCl₃) δ 8.05 (dd, J=9, 6 Hz, 1H), 7.35-7.27 (m, 2H), 4.01 (s, 3H),4.00 (d, J=1 Hz, 3H); ¹⁹F NMR (376 MHz, ¹H decoupled, CDCl₃) δ ⁻123.64(d, J=20 Hz), ⁻128.51 (d, J=31 Hz), ⁻139.59 (dd, J=31, 20 Hz); ¹⁹F NMR(376 MHz, CDCl₃) δ ⁻123.64 (dd, J=19, 9 Hz), ⁻128.51 (dd, J=31, 6 Hz),⁻139.59 (ddd, J=31, 19, 6 Hz).

Preparation of Intermediates: 6-aryl-chloropicolinoyl chlorides Example10 Isopropyl 4,5-dichloro-6-phenylpicolinate

In a 125 mL three-neck round bottom flask was charged potassium fluoridedihydrate (4.52 g, 38.0 mmol), phenylboronic acid (4.88 g, 40 mmol),isopropyl 4,5,6-trichloropicolinate ester (4.28 g, 16.0 mmol), MeCN (60mL), and H₂O (20 mL). The resulting suspension was sparged with N₂ for15 min then bis-triphenylphosphinepalladium (II) chloride (0.45 g, 0.64mmol) added. The resulting yellow suspension was then sparged for 15 minthen heated to 65-68° C. After 1 h of stirring an aliquot (1-2 μL) wastaken and diluted with MeCN (2 mL). The aliquot was analyzed by HPLC bymonitoring the consumption of starting material isopropyl4,5,6-trichloropicolinate ester. After 3 h the reaction was deemedcomplete. The heating mantle was removed and the mixture cooled toambient temperature and diluted with MeCN/EtOAc/H₂O (150 mL, 2/2/1). Thelayers were then separated using a separating funnel and to the organiclayer was added silica gel ≈22 g. The solvent was removed in vacuo andthe solid purified by CombiFlash using a 220 g column. Concentration ofthe aliquots gave a white solid weighing 4.07 g (82%). MP=94-96° C.; ¹HNMR (400 MHz, CDCl₃) δ 8.12 (s, 1H, pyridine H), 7.74-7.71 (m, 2H),7.49-7.46 (m, 3H), 5.31 (h, J=6.4 Hz, 1H), 1.41 (d, J=6.4 Hz, 6H); ¹³CNMR (100.6 MHz, CDCl₃) δ163.1, 158.6, 146.5, 144.3, 137.5, 132.1, 129.6,129.4, 128.0, 125.0, 70.2, 21.8; LRMS Calcd. For C₁₅H₁₃Cl₂N₂O₂: 309.03.Found: 309 (M⁺), 223 (M⁺-CO₂ ^(i)Pr), 188, 152, 125.

Example 11 4,5-Dichloro-6-phenylpicolinic acid

To a 125 mL 3-neck round bottom flask fitted with a condenser, nitrogeninlet, overhead stirring, thermometer and heating mantle was chargedisopropyl 4,5-dichloro-6-phenyl picolinate (7.0 g, 22.5 mmol) andisopropyl alcohol (65 mL). Reaction mixture was heated to 40° C. andpotassium hydroxide (85%, 5.1 g, 77.4 mmol) and water (5 mL) were added.Solids precipitated from the mixture and it became difficult to stir.The mixture was diluted with water (250 mL) to dissolve most of thesolids and allowed to stir at room temperature. Concentrated sulfuricacid (5 mL) was added dropwise to the reaction mixture to achieve a pHof ˜2 and solids precipitated from the mixture. The solids were isolatedby vacuum filtration and washed with water (2×100 mL), then allowed todry in a hood. 5.8 g (96% yield) of 4,5-dichloro-6-phenyl picolinic acidwas isolated as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.28 (s, 1H),7.74-7.60 (m, 2H), 7.59-7.45 (m, 3H), 5.98 (br s, 1H). ¹³C NMR (101 MHz,CDCl₃) δ 162.97, 157.76, 146.26, 144.00, 136.51, 133.84, 130.02, 129.26,128.38, 124.16., MP. 159-160° C.

Example 12 4,5-dichloro-6-phenylpicolinoyl chloride

To a mixture of 4,5-dichloro-6-phenylpicolinic acid (3.00 g, 11.2 mmol)in toluene (40 mL) was added thionyl chloride (1.22 mL, 16.8 mmol) anddimethylformamide (0.04 mL, 0.6 mmol). Reaction mixture was heated at80° C. for 3 h. HPLC analysis of an aliquot treated with methanol anddimethylaminopyridine indicated complete conversion of the startingmaterial. Reaction was allowed to cool to room temperature and thenconcentrated under reduced pressure to provide a white solid. Toluene(40 mL) was added to dissolve the solid and concentrated under reducedpressure and then this process was performed a second time.4,5-Dichloro-6-phenylpicolinoyl chloride was isolated as a white solid(2.84 g, 89% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.14 (s, 1H), 7.83-7.75(m, 2H), 7.55-7.47 (m, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 168.80, 158.88,146.42, 145.21, 136.79, 134.40, 129.98, 129.61, 128.31, 124.74., LRMSCalcd. C₁₂H₆Cl₃NO: 284.95. Found: m/z=285 (M⁺), 250 (M⁺-Cl), 222, 187,152., MP. 106-111° C.

Example 13 Isopropyl 4,5-dichloro-6-(4-methoxyphenyl)picolinate

In a 125 mL three-neck round bottom flask was charged potassium fluoridedihydrate (5.65 g, 60.0 mmol), 4-methoxyphenylboronic acid (3.42 g, 22.5mmol), isopropyl 4,5,6-trichloropicolinate ester (4.00 g, 15.0 mmol),MeCN (72 mL), and H₂O (24 mL). The resulting suspension was sparged withN₂ for 15 min then bis-triphenylphosphinepalladium (II) chloride (0.42g, 0.60 mmol) was added. The resulting yellow suspension was thensparged for 15 min then heated to 60-62° C. After 1 h of stirring analiquot (1-2 μL) was taken and diluted with MeCN (2 mL). The aliquot wasanalyzed by HPLC by monitoring the consumption of starting isopropyl4,5,6-trichloropicolinate ester. After 3 h the reaction was deemedcomplete. The heating mantle was removed and the mixture cooled toambient temperature and diluted with MeCN/PhMe/H₂O (100 mL, 4/3/3). Thelayers were then separated and to the organic layer was added silica gel≈22 g. The solvent was removed in vacuo and the solid was purified byCombiFlash to give a white solid weighing 2.90 g (57%). MP=113-116° C.;¹H NMR (400 MHz, CDCl₃) δ 8.07 (s, 1H, pyridine H), 7.74 (dt, J=9.2, 2.8Hz, 2H), 6.99 (dt, J=8.8, 2.8 Hz, 2H), 5.30 (h, J=6.0 Hz, 1H), 1.41 (d,J=6.0 Hz, 6H); ¹³C NMR (100.6 MHz, CDCl₃) δ 163.2, 160.6, 158.1, 146.4,144.2, 131.7, 131.2, 129.9, 124.4, 113.4, 70.1, 55.3, 21.8; LRMS Calcd.For C₁₆H₁₅Cl₂NO₃: 339.04. Found: 339 (M⁺), 253 (M⁺-O^(i)Pr), 218, 203,182.

Example 14 4,5-Dichloro-6-(4-methoxyphenyl)picolinic acid

To a mixture of isopropyl 4,5-dichloro-6-(4-methoxyphenyl)picolinate(5.25 g, 15.4 mmol) in tetrahydrofuran (40 mL) and water (10 mL) wasadded potassium hydroxide (1.26 g, 22.4 mmol). The reaction was allowedto stir at room temperature for 12 h. After 1 hour of stirring, solidsprecipitated from the mixture. HCl (aq) (2N, 25 mL) was added to thereaction mixture to form a clear biphasic mixture. The mixture was addedto water (75 mL) in a reparatory funnel and extracted with EtOAc (2×75mL). The combined organic layers were washed with water (25 mL) andsaturated NaCl (50 mL) and then concentrated under reduced pressure toprovide 4.57 g (99% yield) of 4,5-dichloro-6-(4-methoxyphenyl)picolinicacid as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.23 (s, 1H), 7.72-7.64(m, 2H), 7.07-6.99 (m, 2H), 3.89 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ162.78, 161.05, 157.26, 146.30, 143.76, 133.54, 130.98, 128.72, 123.45,113.77, 55.48.; mp=164-181° C.

Example 15 4,5-Dichloro-6-(4-methoxyphenyl)picolinoyl chloride

To a mixture of 4,5-dichloro-6-(4-methoxyphenyl)-picolinic acid (4.50 g,15.1 mmol) in toluene (40 mL) was added thionyl chloride (1.65 mL, 22.6mmol) and dimethylformamide (0.06 mL, 0.8 mmol). Reaction mixture washeated at 80° C. for 12 h. HPLC analysis of an aliquot treated withmethanol and dimethylaminopyridine indicated complete conversion of thestarting material. Reaction mixture was allowed to cool to roomtemperature and concentrated under reduced pressure to provide a yellowsolid. Toluene (40 mL) was added to dissolve the solid and concentratedunder reduced pressure and then this process was performed a secondtime. 4,5-Dichloro-6-(4-methoxyphenyl)-picolinoyl chloride was isolatedas a yellow solid (4.64 g, 97% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.09(s, 1H), 7.85-7.77 (m, 2H), 7.06-6.98 (m, 2H). ¹³C NMR (101 MHz, CDCl₃)δ 168.91, 161.06, 158.35, 146.26, 145.13, 133.92, 131.35, 129.16,124.13, 113.70., LRMS. Calcd. for C₁₃H₈Cl₃NO₂: 314.96. Found: m/z=253(M⁺-COCl), 218.

Example 16 Isopropyl 4,5-dichloro-6-(4-chlorophenyl)picolinate

In a 125 mL three-neck round bottom flask was charged potassium fluoridedihydrate (4.52 g, 38.0 mmol), 4-chlorophenylboronic acid (5.00 g, 32.0mmol), isopropyl 4,5,6-trichloropicolinate ester (4.28 g, 16.0 mmol),MeCN (70 mL), and H₂O (23 mL). The resulting suspension was sparged withN₂ for 15 min then bis-triphenylphosphinepalladium (II) chloride (0.45g, 0.64 mmol) added. The resulting yellow suspension was then spargedfor 15 min then heated to 65-68° C. After 1 h of stirring an aliquot(1-2 μL) was taken and diluted with MeCN (2 mL). The aliquot wasanalyzed by HPLC by monitoring the consumption of starting isopropyl4,5,6-trichloropicolinate ester. After 3 h the reaction was deemedcomplete. The heating mantle was removed and the mixture cooled toambient temperature and diluted with MeCN/PhMe/H₂O (80 mL, 2/3/2). Thelayers were then separated and to the organic layer was added silica gel≈22.5 g. The solvent was removed in vacuo and solid purified byCombiFlash to afford after solvent concentration white solid weighing3.44 g (62%). mp=133-135° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.13 (s, 1H,pyridine H), 7.69 (dt, J=8.8, 2.0 Hz, 2H), 7.29 (dd, J=8.4, 2.0 Hz, 2H),5.31 (h, J=6.0 Hz, 1H), 1.41 (d, J=6.0 Hz, 6H, CH₃); ¹³C NMR (100.6 MHz,CDCl₃) δ 162.9, 157.4, 146.6, 144.5, 135.8, 135.7, 132.0, 131.0, 128.3,125.2, 70.3, 21.8; LRMS Calcd. for C₁₅H₁₂Cl₃NO₂: 342.99. Found: 343(M⁺), 257 [(M⁺-CO₂ ^(i)Pr)], 222, 186, 151.

Example 17 4,5-dichloro-6-(4-chlorophenyl)picolinic acid

To a 125 mL 3-neck round bottom flask fitted with a condenser, nitrogeninlet, overhead stirring, thermometer and heating mantle was chargedisopropyl 4,5-dichloro-6-(4-chlorophenyl) picolinate (7.6 g, 22.1 mmol)and isopropyl alcohol (70 mL). Reaction mixture was heated to 40° C. andpotassium hydroxide (85%, 5.1 g, 77.4 mmol) and water (5 mL) were added.Solids precipitated from the mixture and it became difficult to stir.The mixture was diluted with water (250 mL) to dissolve most of thesolids and allowed to stir at room temperature. Concentrated HCl (12 N,5.6 mL) was added dropwise to the reaction mixture to achieve a pH of −2and solids precipitated from the mixture. The solids were isolated byvacuum filtration, washed with water (2×100 mL), and then dried to give7.3 g (108% yield by weight) of 4,5-dichloro-6-(4-chlorophenyl)picolinicacid as a white solid. ¹H NMR (400 MHz, THF/D₂O) δ 8.19 (d, J=11.2 Hz,1H), 7.84-7.73 (m, 2H), 7.50 (dd, J=10.3, 3.5 Hz, 2H). ¹³C NMR (101 MHz,THF/D₂O) δ 167.70, 156.03, 152.40, 143.60, 136.49, 134.76, 131.22,129.24, 128.04, 124.71., MP. 229° C.

Example 18 4,5-Dichloro-6-(4-chlorophenyl)picolinoyl chloride

To a mixture of 4,5-dichloro-6-(4-chlorophenyl)picolinic acid (3.00 g,9.9 mmol) in toluene (25 mL) was added thionyl chloride (1.08 mL, 14.9mmol) and dimethylformamide (0.04 mL, 0.5 mmol). Reaction mixture washeated at 80° C. for 2.5 h. HPLC analysis of the reaction mixturetreated with methanol and dimethylaminopyridine indicated startingmaterial remaining. Reaction mixture was allowed to cool to roomtemperature and additional thionyl chloride (0.5 mL, 6.9 mmol) anddimethylformamide (0.04 mL, 0.5 mmol) were added. Reaction was heated at80° C. for an additional 2 h. Reaction was allowed to cool to roomtemperature and concentrated under reduced pressure to provide a whitesolid. Toluene (40 mL) was added to dissolve the solid and concentratedunder reduced pressure and then this process was performed a secondtime. 4,5-Dichloro-6-(4-chlorophenyl)picolinoyl chloride was isolated asa white solid (3.05 g, 96% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.15 (s,1H), 7.79-7.72 (m, 2H), 7.53-7.46 (m, 2H). ¹³C NMR (101 MHz, CDCl₃) δ168.66, 157.63, 146.48, 145.44, 136.35, 135.10, 134.28, 131.04, 128.63,124.90. LRMS: Calcd. for C₁₂H₅Cl₄NO, 320.91. Found: m/z=257 (M⁺-COCl),222, 207, 186, 151.

Example 19 4,5-Dichloro-6-(4-chloro-2-fluoro-3-methyoxyphenyl)picolinoylchloride

A mixture of 33.5 g (95 mmol) of6-(4-chloro-2-fluoro-3-methoxyphenyl)-4,5-dichloro-2-pyridinecarboxylicacid, 10.2 mL (140 mmol) of thionyl chloride, 0.1 mL ofN,N-dimethylforamide (DMF) and 200 mL of toluene was heated at 75° C.for 5 h. The reaction progress was monitored by conversion of the acidchloride to its methyl ester (one drop of reaction mixture added to 5drops of a 10% wt methanol solution containing4-(dimethylamino)pyridine, briefly heating to reflux, dilution withacetonitrile and injection). LC analysis indicated 8 area % remainingcarboxylic acid and 3 area % of an unidentified closely followingproduct. Another 5 mL of thionyl chloride and 0.1 mL of DMF was added,and heating was continued for an additional 2 h. After stirring at roomtemperature overnight, the reaction mixture was filtered to remove asmall amount of an insoluble material. The filtrate was concentrated invacuo, and toluene added twice and re-concentrated in vacuo to removeresidual thionyl chloride. The white solid obtained (38.6 g) was driedin a vacuum oven at 40° C. to give 33.3 g of a white solid, mp 134-136°C. LC internal standard analysis (conversion to its methyl ester asdescribed above) indicated 98.1 wt %. EIMS m/e (relative intensity) 369(4Cl, 80), 332 (3Cl, 38), 304 (3Cl, 82), 269 (2Cl, 100), 254 (2Cl, 30),226 (2Cl, 73), 191 (30), 156 (46); ¹H NMR (400 MHz, CDCl₃) δ 8.23 (s,1H), 7.32 (dd, J=8, 2 Hz, 1H), 7.15 (dd, J=8, 7 Hz, 1H), 4.02 (dd, J=1Hz, 3H); ¹⁹F NMR (376 MHz, ¹H decoupled, CDCl₃) δ 126.83.

The embodiments described above are intended merely to be exemplary, andthose skilled in the art will recognize, or will be able to ascertainusing no more than routine experimentation, numerous equivalents ofspecific compounds, materials, and procedures. All such equivalents areconsidered to be within the scope of the invention and are encompassedby the appended claims.

1-16. (canceled)
 17. A process for the preparation of a compound of the Formula II:

wherein R is selected from the group consisting of halo; alkyl; cycloalkyl; alkenyl; alkynyl; alkoxy and aryl substituted with from 0 to 5 substituents independently selected from the group consisting of halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy and C₁-C₄ haloalkoxy; R¹ is selected from the group consisting of H; alkyl; cycloalkyl; alkenyl; alkynyl; unsubstituted or substituted C₇-C₁₁ arylalkyl; and aryl substituted with from 0 to 5 substituents independently selected from the group consisting of halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy and C₁-C₄ haloalkoxy; m is 0, 1, 2 or 3; and n is 0, 1, 2, 3 or 4; wherein the sum of m and n is between 1 and 4; which comprises (a) fluorinating a compound of Formula A:

with a source of fluoride ion to produce a compound of the Formula I:

wherein R is selected from the group consisting of halo; alkyl; cycloalkyl; alkenyl; alkynyl; alkoxy and aryl substituted with from 0 to 5 substituents independently selected from the group consisting of halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy and C₁-C₄ haloalkoxy; m is 0, 1, 2 or 3; and n is 0, 1, 2, 3 or 4; which further comprises (b) reacting the compound for Formula I with a source of R¹OH to produce a compound of Formula II.
 18. The process of claim 17 wherein R¹ is selected from the group consisting of H; alkyl; cycloalkyl; alkenyl; alkynyl; and aryl substituted with from 0 to 5 substituents independently selected from the group consisting of halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy and C₁-C₄ haloalkoxy.
 19. The process of claim 17 wherein step (b) is performed in the presence of a base. 20-25. (canceled)
 26. The process of claim 17, wherein fluorinating a compound of Formula A is performed in the presence of a catalyst, wherein the catalyst is selected from the group consisting of a crown ether, a phosphonium halide, a polyether, a phosphazenium salt, and a tetra-substituted ammonium halide.
 27. The process of claim 26, wherein the catalyst is a crown ether.
 28. The process of claim 27, wherein the crown ether is 18-crown-6.
 29. The process of claim 17, wherein the source of fluoride ion is a metal fluoride.
 30. The process of claim 29, wherein the metal fluoride is selected from the group consisting of sodium fluoride, potassium fluoride and cesium fluoride.
 31. The process of claim 30, wherein the metal fluoride is potassium fluoride.
 32. The process of claim 17, wherein step (a) includes a solvent, wherein the solvent is an alkyl nitrile or an alkyl sulfone.
 33. The process of claim 32, wherein the solvent is acetonitrile or sulfolane.
 34. The process of claim 17, wherein the source of fluoride ion is potassium fluoride, and wherein step (a) is conducted in the presence of a crown ether and a solvent.
 35. The process of claim 34, wherein the solvent is acetonitrile or sulfolane.
 36. The process of claim 19, wherein the base is a trialkylamine base.
 37. The process of claim 36, wherein the trialkylamine base is triethylamine. 